The proposed studies will attempt to elucidate the contribution of the human immunodeficiency virus (HIV) LTR to pathogenesis using SIV as a model system. The investigator will attempt to assess whether LTR mutations between phenotypically distinct viruses lead to "genetic" and/or "cell-type/species-specific" differences in viral gene expression by measuring relative levels of LTR-driven expression of an indicator gene (CAT/SEAP). The applicant will attempt to correlate such differences with other parameters, including LTR-binding by cellular proteins and viral pathobiology. Site-directed mutagenesis will be used to assign significance to individual mutations between LTRs. Data correlation will be facilitated by using the same panel of cells for all studies, that is, peripheral blood mononuclear cells (PBMC), lymphoid cell lines, enteric macrophages and lymphocytes from several primate species, as well as human cell lines of various lineage. Finally, the applicant proposes to investigate whether LTR changes are associated with pathogenesis of other SIV isolates. LTRs will be cloned from necropsied tissues and /or "post-disease onset" PBMC specimens from animals that succumbed to fatal SIVsmm infection, as well as serial blood samples (harvested before and after onset of disease). Comparative sequence analysis will then be performed.